[Molecular mechanism of vascular calcification.]

Intimal and medial calcification are increased with type 1 and type 2 diabetes, metabolic syndrome, chronic kidney disease, and ageing. There are several biological mechanisms through which vascular calcification increases all-cause mortality and atherosclerotic plaque rupture. Arterial medial calcification increases arterial stiffness that causes systolic hypertension and diastolic dysfunction and heart failure. In contrast, arterial intimal calcification is strongly associated with atherosclerotic plaque burden, predicting adverse arterial events. In particular, micro-calcifications within the fibrous caps are through to increase local stress and risk of plaque rupture. While vascular calcification has originally through to be a passive process, it has become increasingly clear that calcification of both intimal and medial layers is an active and tightly regulated process in which dynamic phenotypic changes of vascular smooth muscle cells plays a major role. Interestingly, the driving factors for medial and intimal calcification differ. Whilst uremia and senescence, high serum calcium and phosphate levels drives medial calcification, inflammation and oxidative stress are critical for intimal calcification. Despite the different drivers and environmental cues, the medial and intimal arterial calcification shares common intracellular signaling cascades to promoter cellular reprogramming and phenotypic switching. Recent studies employing new technologies demonstrate that calcifying extracellular vesicles(EVs)that have specific mineralization-promoting cargos such as tissue nonspecific alkaline phosphatase(TNAP), annexins Ⅱ and Ⅵ, are released from vascular smooth muscle, macrophages, and valvular interstitial cells, and serve as calcifying foci. Recent study identified a specific trafficking protein, sortilin, as a key player in the formation of calcifying EVs secreted by vascular smooth muscle cells. Research on aortic valve calcification using spatiotemporal multi-omics identified many secreted and structural matrix proteins not previously implicated in valvular calcification, and revealed that inflammation is likely to be a significant contributor regardless of the layers and stages of the aortic stenosis progression. Increased understanding of the precise molecular mechanisms of phenotypic switching of vascular smooth muscle offers the best chance to identify the potential drug targets for vascular calcification.